tbuckley/cabot-search huggingface dataset:
EXTH-43. TARGETING THE DNA DAMAGE RESPONSE THROUGH COMBINATION MDM2 AND AKT INHIBITOR THERAPY IMPROVES TEMOZOLOMIDE EFFECTIVENESS IN CHEMO-RESISTANT GLIOBLASTOMA
Authors: Jenna Koenig, Barbara Bailey, Anthony Alfonso, M Reza Saadatzadeh, Khadijeh Bijangi-Vishehsaraei, Pankita Pandya, Nur Damayanti, Erika Dobrota, Courtney Young, Harlan Shannon, Karen Pollok
Journal: Neuro-Oncology (2023)

Abstract Temozolomide remains the lone pharmacotherapeutic option for glioblastoma (GBM), yet the development of resistance to temozolomide has been a major challenge contributing to the persistent median &amp;lt; 2-year survival for patients after diagnosis. Tumor heterogeneity and induction of treatment response networks, such as the DNA damage response (DDR), are major contributors to temozolomide resistance in GBM. Targeting DDR treatment response networks, such as the MDM2/p53/p73 and PI3K/AKT/mTOR networks, with small-molecule inhibitors (SMIs) presents an opportunity to disrupt resistance mechanisms and enhance temozolomide efficacy. We utilized a triple drug combination of clinically relevant concentrations of the blood-brain-barrier penetrant SMIs of AKT (ipatasertib; GDC-0068) and MDM2 (idasanutlin; RG7388) with temozolomide to evaluate this targeted strategy using the recurrent, temozolomide-resistant, p53wt GBM10 xenoline. Proliferation studies demonstrated dose-related additive to synergistic inhibition of proliferation at clinically relevant concentrations of ipatasertib and idasanutlin. Further, IncuCyte live-cell imaging demonstrated dose-and time-related growth inhibition of these GBM cells and apoptosis marked by increased cleaved caspase 3 expression following the temozolomide+idasanutlin+ipatasertib triple combination treatment. Cells treated with temozolomide+idasanutlin+ipatasertib also displayed senescence phenotypes, with increased cell cycle arrest and elevated expression of SPiDER β-Gal expression and cell-cycle inhibitors such as p53 and p21. Experiments are in progress to determine the extent to which the effects of temozolomide+idasanutlin+ipatasertib combination therapy are dependent on p53 using siRNA knockdown of p53. In the present study, targeting the temzolomide-induced DNA damage response with idasanutlin+ipatasertib increased the effectiveness of temozolomide. These results indicate that this triple combination may be a promising approach to improving patient outcomes in temozolomide-resistant GBM.
INNV-21. EXTENDED SURVIVAL OF RECURRENT ANAPLASTIC OLIGODENDROGLIOMA PATIENT WITH GOOD FUNCTIONAL STATUS ON LONG TERM PEMBROLIZUMAB AND BEVACIZUMAB THERAPY - A CASE REPORT
Authors: Matthew Moldenhauer, Joon Myung, Beverly Dan Fu, Xiao-Tang Kong
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION Anaplastic oligodendroglioma (AO) is a rare high-grade glioma. Standard of care include resection, radiotherapy followed by chemotherapy. However, effective treatment for recurrent AO is limited. Here we report pembrolizumab (Pembro) + bevacizumab (Bev) therapy for recurrent AO. CASE A 55-year-old male had a brain mass discovered on MRI in 2012 and received no treatment until resection in 2014. He underwent second tumor resection in late 2016 and pathology demonstrated an AO, WHO grade 3. He received radiation followed by PCV regimen in 2017. Ten months later in March 2018, he had tumor progression on PCV. Temozolomide was started. Two months later, Bev (10 mg/kg) was initiated in May 2018 due to further progression. After 12 months of Bev therapy, in mid-2019, Pembro was added due to new and enlarged lesions on MRI. After 18 months of q-3-week Bev (10mg/kg) + Pembro, Bev was on hold in December 2020 due to multiple TIAs. Single agent Pembro was continued for 6 months until April 2021 when his brain MRI showed increased enhancement. Then q-3-week Bev was resumed at a reduced dose (7.5mg/kg). These dual agents continued for 14 months until June 2022 when Bev dose was further reduced to 5mg/kg due to side effect. Bev was on hold again in December 2022 due to high Urine Protein/Creatinine ratio. Single agent Pembro was continued until May 2023 when lower dose Bev (2.5mg/kg) was resumed after MRI showed one subcentimeter new lesion. The small lesion is stable again on q-3-week 2.5 mg/kg Bev+Pembro. The patient has been clinically functional on Bev+Pembro treatment. DISCUSSION Four years of adjuvant pembrolizumab and tailored dose of bevacizumab have resulted in long term repeated stabilization of recurrent AO. The dose and duration of bevacizumab use need to be tailored to minimize adverse effects and to maintain positive effects.
NCMP-13. CONCURRENT WOUNDED GLIOMA SYNDROME AND DISTANT WOUNDED GLIOMA SYNDROME FOLLOWING A GROSS TOTAL RESECTION OF GLIOBLASTOMA MULTIFORME – A CASE REPORT
Authors: John Michael Calubayan, Paul Vincent Opinaldo
Journal: Neuro-Oncology (2023)

Abstract Surgery is the initial form of treatment for glioblastoma, and a maximum resection without impairing neurological function improves survival. Wounded Glioma Syndrome (WGS) is a clinical picture observed after the resection of high-grade tumors. This syndrome, developing within hours or a few days after glioma surgery, is characterized by hemorrhage into the surgical bed and cerebral edema, and at times occurring in areas distant from the site of the resection, i.e., Distant WGS. We report a case of an elderly male presenting with an acute-onset left leg weakness, with a large peripherally-enhancing mass with central non-enhancement suggestive of necrosis in the right frontal lobe. A gross total resection of the tumor was done, and the histopathologic evaluation yielded a high-grade glioma, favoring a diagnosis of Glioblastoma WHO Grade-IV. During the postoperative period, he was drowsy and was able to move the right extremities. He had a series of generalized tonic-clonic seizures three hours after the operation. After eight hours, the patient became comatose with signs of increasing intracranial pressure. A cranial CT revealed diffuse cerebral edema, and hemorrhage into the operative site in the right frontal lobe, as well as subarachnoid hemorrhages in the bilateral fronto-parietal sulci. There were also small hemorrhages seen in the left caudate head, midbrain and left hemipons. Death occurred the following day. This case report demonstrates an unusual case of a WGS with a concurrent Distant WGS in the brainstem after a gross total resection of a frontal lobe glioma. This case shows a significant uncommon sequela that a patient undergoing glioma surgery can present, leading to rapid deterioration and death. Resection of a glioma carries a significant risk, and its impact in the immediate postoperative period merits evaluation when planning the perioperative management, taking prompt action if these syndromes occur.
NIMG-18. MULTI-PARAMETRIC MRI AND SPECT ASSESSMENT OF TREATMENT DOSE AND EFFICACY IN RESPECT-GBM FOR RECURRENT GLIOBLASTOMA (RGBM)
Authors: Shiliang Huang, Andrew Brenner, Ande Bao, Joel Michalek, Melissa Moore, Marc Hedrick, Norman LaFrance
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND We have previously shown a dose-dependent association with survival for patients receiving Rhenium-186-nanoliposome (186RNL) for rGBM. This study aim, applying 3D-dosimetry and advanced-MRI features to outcome assessment, was to extend those findings. METHODS SPECT/CT images were acquired at mid-fusion, end-of-infusion, 24-hour, 120-hour, and 192-hour post-186RNL infusion. Baseline MRI was performed within 7days of treatment, at 28d, and every 56d until progression with: T1-3D pre-/post-contrast agent, DSC, DWI. SPECT images were processed using MIM software with treatment volumes corresponding to the 100Gy isodose curve exported as treatment-ROI. Difference (delta T1) between standardized pre-contrast (T1) and post-contrast (T1_C) anatomic images were used to measure tumor volume (IB Rad Tech). Within the tumor, various MRI-derived parameters, such as standardized-relative-cerebral-blood-volume (srCBV), time to maximum (Tmax), time to peak (TTP), were calculated. RESULTS Perfusion analysis(n=8) revealed significant decreases in the mean nrCBF, nrCBV, rCBF, rCBV, and srCBV with dose [nrCBF: -0.25 95% CI -0.37 to -0.14, p=0.005, nrCBV: -0.23 95% CI -0.34 to -0.13, p=0.005, rCBF: -3.5 95% CI -5.37 to -1.63, p=0.01, rCBV: -11.91 95% CI -20.45 to -3.38, p=0.03, srCBV: -0.14 95% CI -0.23 to -0.05, p=0.02], and a significant increase in the mean Tmax [1.88 95% CI 0.58 to 3.17, p=0.03]. The mean volume (n=10) not covered by treatment (-1.59 95% CI -4.81 to 1.63, p=0.36), Tumor volume (-0.76 95% CI -5.23 to 3.72, p=0.75), Treated volume (3.31 95% CI -0.44 to 7.06, p=0.12), and Tumor Volume covered by treatment (0.84 95% CI -1.2 to 2.87, p=0.44) did not vary significantly with dose although may gain significance with a larger data set. CONCLUSION MRI radiographic features proved valuable in assessing treatment efficacy and guiding treatment considerations. Image processing is ongoing, and the complete data set will be presented.
EXTH-38. VELCRIN MOLECULAR GLUES INDUCE CELL DEATH IN GLIOBLASTOMAS WITH HIGH <i>PDE3A</i> AND <i>SLFN12</i> EXPRESSION
Authors: Elisa Aquilanti, Silvia Goldoni, Andrew Baker, Kristina Kotynkova, Sawyer Andersen, Galen Gao, Andrew Cherniack, Martin Lange, Charlotte Kopitz, Philip Lienau, Timothy Lewis, Marine Garrido, Stefan Gradl, Henrik Seidel, Keith Ligon, Patrick Wen, Matthew Meyerson, Heidi Greulich
Journal: Neuro-Oncology (2023)

Abstract Velcrins are molecular glues that kill cells by inducing the formation of a protein complex between the RNase, SLFN12, and the phosphodiesterase, PDE3A. Formation of the complex activates SLFN12, which cleaves tRNALeu(TAA) and induces apoptosis. Velcrins such as the clinical investigational compound, BAY 2666605, were found to have activity across multiple solid tumor cell lines from the Cancer Cell Line Encyclopedia (CCLE), including glioblastoma cell lines. We therefore aimed to characterize velcrins as novel therapeutic agents in glioblastoma. We measured PDE3A and SLFN12 expression levels in commercially available glioblastoma cells as well as glioblastoma neurospheres from the Center for Patient Derived Models at Dana Farber Cancer Institute. We identified velcrin-sensitive glioblastoma cell lines and neurospheres, and determined that velcrin response is highly correlated with PDE3A expression. We also determined that sensitive cells exhibit a reduction in nascent polypeptide formation upon velcrin treatment, which is rescued by CRISPR-induced knockout of PDE3A. To assess velcrin efficacy in vivo, we measured central nervous system and plasma levels of the velcrin, BAY 2666605, and determined that it freely crosses the blood brain barrier. We also determined that twice daily dosing of BAY 2666605 elicits full tumor regression in an orthotopic glioblastoma xenograft model, with sustained complete responses after treatment withdrawal. Lastly, we demonstrated that the velcrins BAY 2666605 and BAY 2501293 induce tumor regression in biomarker-positive subcutaneous glioblastoma patient-derived xenograft models. In summary, our data demonstrates that velcrins have anti-tumor activity in preclinical models of glioblastoma, warranting further investigation as potential therapeutic agents.
EXTH-41. COMBINATION TREATMENT OF CALCIUM CHANNEL ANTAGONIST MIBEFRADIL ENHANCES THE EFFECT OF HYDROXYUREA AT THERAPEUTIC RANGES IN HIGH-GRADE MENINGIOMA <i>IN VITRO</i>
Authors: Erik White, Michael Prabhu, Jigisha Thakkar, Kevin Barton, Vikram Prabhu, Erika Piedras-Renteria
Journal: Neuro-Oncology (2023)

Abstract High-grade meningiomas (MNs), WHO Grade II- III, are highly aggressive brain tumors that are difficult to treat. Standard chemotherapy agents are, at best, moderately effective in treating high-grade MNs. There is great interest in developing combinatorial drug treatment regimens to enhance the effects of standard chemotherapy. Many cancer types, including brain tumors, have an increase in the expression of voltage-gated calcium channels (VGCCs). These channels are involved in the regulation of cell cycle, proliferation, and apoptosis, among other functions. FDA-approved VGCC antagonists nimodipine (NIMO) and mibefradil (MIB) target two different VGCCs, L- and T-type channels, and have been of great interest for their use in combination therapy in other cancers. We sought to determine the efficacy of chemotherapy agents tested at clinically relevant concentrations for the treatment of high-grade MNs alone or in combination with NIMO or MIB. We cultured CH-157MN and IOMM-Lee MN cells and assessed their cell survival, apoptosis, and proliferation in the presence of temozolomide, octreotide, sunitinib, or hydroxyurea (HU). We confirmed that HU (150 µM) was the most efficacious chemotherapy agent, decreasing cell viability at therapeutic ranges. Monotherapy treatment with 2 or 4 µM MIB significantly decreased cell viability in both cell lines, whereas 1 µM NIMO only affected IOMM-Lee cells. The combination of HU and MIB further decreased cell viability but only in the most aggressive cell line, IOMM-Lee, whereas NIMO did not enhance HU’s ability to decrease cell survival. Remarkably, we detect an enhancement of HU’s effect by MIB when both agents are used within therapeutic ranges, as reported by pharmacokinetic studies. Here we demonstrate for the first time that T-type calcium channels play an important role in MN survival. The combination of HU and MIB suggests their use could be a promising treatment for high-grade MN.
NIMG-16. THE PROGNOSTIC VALUE AND BIOLOGICAL SIGNIFICANCE OF MRI CE-T1-BASED RADIOMICS MODELS IN CNS5-IDENTIFIED GBM
Authors: Mingwei Zhang, Xuezhen Wang, Xiaoxia Li, Shan Li, Qiuyuan Yue, Jinsheng Hong
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Following the publication of the 2021 WHO Classification of CNS Tumors (Fifth Edition) (CNS5), prognostic markers to guide the individualized treatment of patients with glioblastoma (GBM) (CNS5) need to be explored. Radiomics is a non-invasive, reproducible, and cost-effective method that has been used in the prognostic assessment of multiple solid tumors. The prognostic value and biological significance of MRI T1 - weighted enhancement (CE-T1) - based radiomics models in GBM (CNS5) has not been reported. METHODS The tumor region of MRI CE-T1 phase was segmented, and radiomics features were extracted. The consistency analysis, univariate Cox regression and two machine learning algorithms were used for feature reduction. Then, the radiomics prognostic model was established to calculated the radiomics score (RS). The independent external validation was independently verified using the bicenter radiotherapy cohorts. The enrichment analyses of the differential genes between RS-high and -low groups were implemented to explore the biological significance. RESULTS A prognostic model composed of six radiomics features were built. A high RS (HR=3.718, 95%CI: 2.222−6.220, P&amp;lt; 0.001) was an independent risk factor for overall survival (OS). The result was externally validated by two cohorts. Through biological significance exploration, RS was found to be significantly correlated with DNA repair (P=0.009) and glycolysis (P=0.001) pathway enrichment scores. RS was associated with γδT cell infiltration and the expression of LAG3. CONCLUSION The MRI CE-T1 based radiomics prognostic models constructed can predict GBM (CNS5) prognosis noninvasively and effectively, which is relevant to DNA repair, and may guide the screening of radiosensitive populations.
NCMP-08. TREATMENT OF PITUITARY METASTASIS: A SINGLE CENTER EXPERIENCE AND SYSTEMATIC LITERATURE REVIEW
Authors: Sabrina Begley, Kaiyun Yang, Vincent Ye, Daniel Lynch, Enrique Gutierrez, Mark Bernstein, Gelareh Zadeh, David Shultz, Paul Kongkham
Journal: Neuro-Oncology (2023)

Abstract PURPOSE To understand the natural history and optimal treatment strategy for pituitary gland metastasis. METHODS We performed both a retrospective chart review of patients treated at our institution and a scoping review of the topic. RESULTS The retrospective review identified seven patients with an average age of 59.6. Primary histologies included breast cancer (4), melanoma (1), renal carcinoma (1), and sarcoma (1). Two patients had anterior pituitary endocrine dysfunction, one of whom was the only patient with visual symptoms. All patients were treated with radiosurgery and two also underwent surgical resection. Overall survival ranged from 6.5 – 117 months. We identified 166 patients from 71 studies in our literature review. The most common primary cancer was lung (27.7%), followed by breast (18.7%) and renal (14.5%) cancer. 107 presented with endocrine dysfunction; with 41 cases of diabetes insipidus and 55 cases of hypopituitarism. 110 presented with visual compromise. 107 patients received radiotherapy, 96 underwent surgical resection and 44 received systemic chemotherapy/immunotherapy. Surgery was significantly associated with an increased likelihood of vision improvement and a decreased likelihood of endocrine normalization. Radiographic regression predicted visual improvement. Median overall survival was 9.9 months (range: 0.2 – 96). CONCLUSIONS Our scoping review showed that both radiosurgery and surgical resection have been frequently used to treat pituitary metastases with good response. Vision improvement is more likely to happen following surgical resection. Despite treatment and radiographic response, patient survival remains less than a year.
INNV-37. BELZUTIFAN IMPACT ON VHL-ASSOCIATED CNS HEMANGIOBLASTOMAS
Authors: Abigail Demers, Amal Abukhdeir, Tyra Gatewood, Antoniya Marinova Doynova, Jad Chahoud, Phillippe Spiess, Mokenge Malafa, David Iacono, Solmaz Sahebjam, Nam Tran, Sepideh Mokhtari
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION CNS hemangioblastomas are a leading cause of morbidity and mortality among patients with Von Hippel-Lindau (VHL) disease. Belzutifan, a selective hypoxia-inducible factor (HIF-2a) inhibitor, has been approved for the treatment of hemangioblastomas in VHL patients; however, long-term efficacy and safety data are lacking. METHODS The authors performed a retrospective chart review of all type Ia VHL with symptomatic CNS hemangioblastomas who were treated with Belzultifan at the Moffitt Cancer Center from August 2021 to June 2023. Patient demographics, clinical characteristics, tumor characteristics, and complications were assessed. Patients were re-evaluated with repeat CNS imaging every 3-6 months. RESULTS Eleven patients were identified. Median age is 35 years (IQR: 24-56) and 4/11 patients (36%) are female. Eight out of 11 patients had accessible genetic testing and 87.5% had a missense mutation in the VHL gene. Two patients (18%) had pathology-proven RCC and no patients had pheochromocytomas. One patient (9%) had complete response, eight (73%) had partial response, and two patients (18%) had stable disease at 6 months. Treatment was stopped on 8 patients once they reached stable response to treatment, with 1 patient at 6 months (12.5%), 5 patients at 1 year (62.5%), and 2 patients at 16 months (25%). Five out of 8 patients (62.5%) had sustained response (≥ 3 months) during the time Belzutifan was held. Treatment was restarted on the 3 patients who had progression of disease and all 3 had positive response to treatment at 3 months. All patients had anemia (CTCAE grade 1-2), but did not require blood transfusions, and 1 patient had visual disturbances after restarting Belzutifan. CONCLUSION All patients responded positively to Belzutifan based on surveillance CNS imaging, with no major side effects. The majority of patients had sustained response after having stopped the drug for 3 months.
MODL-20. PRECLINICAL MODELING OF LASER INTERSTITIAL THERMAL THERAPY IN MURINE BRAIN TUMORS FOR TRANSLATIONAL IMMUNO-ONCOLOGY
Authors: Aden Haskell-Mendoza, Lucas Wachsmuth, Richard Tyc, Peter Fecci
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION Cytoreductive surgery is a cornerstone of management for intracranial tumors. However, resection may remove an important source of neoantigen. In the case of laser interstitial thermal therapy (LITT), ablated tumor remans in situ, allowing for an anti-tumor immune response. To characterize these phenomena, we developed a murine model of LITT for use with syngeneic brain tumor cell lines. RESULTS &amp; METHODS To establish anatomical boundaries for our ablation, we characterized our CT-2A glioma model on T2 MRI, selecting 10 days post-implantation for LITT based on lesion size. We simultaneously implanted a 400 μm laser fiber and thermocouple probe into the center and edge of the target volume, respectively, for simultaneous ablation and temperature monitoring. Using a clinical 1064 nm Nd:YAG laser, we first performed a dose titration of laser power/time in normal mouse brains, finding that doses above 1.5 W for 60s produced cavitary lesions with charring that resulted in death at 24h post-LITT. We therefore selected 1 W for 60s as a safe laser power dose in our tumor model. Ablations at this setting rapidly heated the lesion edge to a peak temperature of mean 43.79 ± 2.993 °C, sparing the surrounding brain. MRI imaging at 1, 3, and 7 days post-LITT revealed expansile T2 hyperintense lesions that resolved over time, with hemorrhage and necrosis on H&amp;E. LITT increased survival to 28 from 25.5 days (vs sham, P = 0.0172). CONCLUSIONS Our model successfully recapitulates the essential clinical features of LITT: a cytoreductive survival benefit; lesion expansion on MRI; and focal necrosis with hemorrhagic vasculature on H&amp;E. This model is well suited for study of LITT-adjunctive interventions and characterization of the immunobiology of hyperthermia.
PATH-27. DROPLET DIGITAL PCR ENHANCES DETECTION OF HOTSPOT MUTATIONS IN CIRCULATING TUMOR DNA FROM CEREBROSPINAL FLUID OF PATIENTS WITH HIGH-GRADE GLIOMA
Authors: Marlene Tartaro, Subhiksha Nandakumar, Charli Ann Hertz, Bridget Holle, Katherine Hill, Maria Lapshina, Andrea Farina, Maria Arcila, Alexandra Miller, Ingo Mellinghoff
Journal: Neuro-Oncology (2023)

Abstract Molecular profiling of circulating tumor DNA (ctDNA) from cerebrospinal fluid (CSF) has the potential to enhance diagnosis, prognosis, and longitudinal monitoring for glioma patients through a minimally invasive approach. We previously detected somatic mutations from gliomas in CSF samples using MSK-IMPACT™, a 505-gene FDA-authorized next-generation DNA sequencing panel, and detected tumor-derived mutations in 50% of samples of patients with high-grade gliomas (HGG). To investigate whether we could enhance sensitivity of CSF ctDNA profiling and biomarker detection, we tested MSK-IMPACT™ pre-capture NGS residual DNA libraries from 43 CSF ctDNA samples by droplet digital PCR (ddPCR) for detection of key recurrent alterations in IDH1, BRAF, TERT, H3F3A, and TP53 using previously validated probes. Residual libraries contained a median of 18.0ng of DNA library (range, 0.0153-18.0ng). Of the 7 samples positive for IDH1 R132H, TERT C228T, or TERT C250T mutations in MSK-IMPACT™, we found that ddPCR accurately detected all mutations (7/7, 100%), confirming sensitivity of ddPCR in CSF ctDNA. We also tested 36 mutation-negative samples by MSK-IMPACT™ for the corresponding undetected mutations, of which 7 were tested for two mutations. Overall, ddPCR detected 41.9% (18/43) of previously undetected mutations. Specifically, we found that ddPCR rescued hotspot mutations such as BRAF V600E (2/3, 66.7%), IDH1 R132G/H (3/8, 37.5%), TERT C228T (11/26, 42.3%), and TERT C250T (2/4, 50.0%). Collectively, our results suggest that a combined-modality approach involving MSK-IMPACT™ and ddPCR enables comprehensive assessment of limited CSF ctDNA samples with high sensitivity and provides a minimally invasive methodology to molecularly profiling glioma.